Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracellular calcium (Ca2+) is the major physiological regulator of parathyroid function; high Ca2+ decreases PTH secretion as well as reduces cAMP accumulation. There is an increasing body of evidence suggesting the presence of a receptor-like mechanism at the surface of the parathyroid cell which mediates these and other actions of Ca2+. In the present studies we used the lectin Concanavalin-A (Con-A) to investigate the possible role of carbohydrate moieties in the regulation of cAMP metabolism by Ca2+ in bovine parathyroid cells, which is thought to involve inhibition of adenylate cyclase via activation of the guanine nucleotide regulatory protein Gi. Pretreatment of parathyroid cells with Con-A for 15-60 min significantly reversed the inhibitory effect of high Ca2+ on dopamine-stimulated cAMP accumulation, reducing the inhibition at 3 mM Ca2+ from 70 +/- 3% to 30 +/- 3%. This effect was also observed in the absence of preincubation and with concentrations of Con-A as low as 40 micrograms/ml and was reversed by alpha-methyl-D-glucoside, a specific antagonist of the lectin. The lectin also reversed the inhibitory effects of Ca2+ (2-3 mM) on cAMP accumulation stimulated by isoproterenol and forskolin to a comparable extent. Prostaglandin F2 alpha-induced inhibition of cAMP accumulation (likewise mediated by Gi) was, however, not reversed by Con-A, suggesting that the lectin did not have a generalized effect on the cell surface or on receptors inhibiting adenylate cyclase. Moreover, fluoride-induced inhibition of cAMP accumulation was not reversed by Con-A, providing additional evidence that the lectin did not act at or distal to Gi (i.e. modulate Gi, adenylate cyclase, and/or phosphodiesterase). The present study suggests that Con-A may modulate the actions of extracellular Ca2+ on parathyroid secretion, possibly modifying the interaction of Ca2+ with the cell surface by affecting carbohydrate moieties that seem to be important in the Ca2(+)-sensing process. The structural element involved in Ca2+ sensing in the parathyroid cell may be a glycoprotein or closely associated with glycoproteins with carbohydrate chains containing alpha-methyl-D-glycoside.
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PMID:Effect of the lectin concanavalin-A on calcium-regulated adenosine 3',5'-monophosphate accumulation in bovine parathyroid cells. 215 77

Epidermal cells contain 4 separate surface receptors which are linked to adenylate cyclase. Activation of any one of these receptors leads to the accumulation of cAMP within the cell which in turn leads to the activation of cAMP-dependent protein kinase. The levels of cAMP accumulation within the cell caused by the 4 activators are not the same. Epinephrine, histamine, adenosine, and prostaglandins of the "E" series cause easily measurable concentrations of cAMP within 5 min of exposure. Prostaglandin F2 alpha causes only a small nonsignificant increase. Similarly, 2 phosphodiesterase inhibitors, which inhibit the breakdown of cAMP formed within the cell, differ in their ability to accumulate cAMP when cells are exposed to these agents alone. Isobutylmethylxanthine causes a measurable increase in cAMP, while theophylline, a weak inhibitor of phosphodiesterase, gives a nonsignificant increase in cAMP. Recently, experiments have shown that agents that give only slight increases in cAMP by biochemical measurements, that is, prostaglandins F2 alpha and theophylline, are equally able to activate protein kinase within the cell. Since activation of protein kinase is the only mechanism for an increase in cAMP to have a physiologic effect, all of these agents that do activate protein kinase should cause physiologic effects. Using an explant culture system, we show in this paper that this supposition is correct and that all agents that activate protein kinase do result in inhibition of mitotic activity regardless of whether or not they are able to raise cAMP to a level that can be biochemically measured as being significantly different from the baseline value.
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PMID:Agents that activate cyclic AMP-dependent protein kinase inhibit explant culture growth and mitotic activity. 619 22

The beta-adrenoceptor agonists, isoprenaline, salbutamol and salmeterol, the non-selective phosphodiesterase (PDE) isoenzyme inhibitors, theophylline, trequinsin; the PDE3 isoenzyme inhibitor, milrinone; the PDE3/4 isoenzyme inhibitor, benzafentrine; and the PDE4 isoenzyme inhibitors, denbufylline, nitraquazone, RP 73401, Ro-20-1724, rolipram and tibenelast all induced concentration-dependent reversal of prostaglandin F2alpha-induced contraction of guinea-pig superfused trachea in vitro. The relaxant response of the non-selective PDE isoenzyme inhibitor trequinsin was slow in onset and demonstrated very slow recovery, similar to that observed with the long-acting beta2-adrenoceptor agonist, salmeterol and the PDE4 inhibitor, RP 73401. The relaxant agonists also significantly reversed bombesin-induced bronchospasm in anaesthetised guinea-pigs and there was a highly significant correlation between the ability of drugs to reverse PGF2alpha-induced contraction of guinea-pig isolated trachea in vitro and bombesin-induced bronchoconstriction in vivo. Furthermore, both salmeterol and trequinsin demonstrated long lasting bronchodilator responses consistent with the in vitro data. These results show that PDE isoenzyme inhibitors demonstrate different pharmacodynamic profiles that is not determined by PDE4 inhibitory potency and indicate that other factors may be important in this regard.
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PMID:The effect duration of selective phosphodiesterase inhibitors in the guinea pig. 951 52

Chronic hypoxia is associated with altered pulmonary vasoreactivity, and it has been suggested that an increased response to voltage-dependent vasodilators may relate to enhanced Ca++ entry via voltage-dependent channels, secondary to depolarization. Few studies have been performed on small pulmonary arteries, and it is unknown whether they are depolarized after chronic hypoxia. We examined the resting membrane potential, and the actions of voltage-dependent (verapamil, levcromakalim) and -independent (isoproterenol, forskolin, papaverine) vasodilators in small ( approximately 300 microm internal diameter) pulmonary arteries from chronically hypoxic rats. The resting membrane potential was more positive in arteries after chronic hypoxia (control: -60 +/- 0.5 mV; hypoxic: -54.4 +/- 1.1 mV; P < .01), and this was reflected by a shift to the left of the response curves for K+ and 4-aminopyridine. In arteries constricted with prostaglandin F2alpha the response to verapamil and levcromakalim was increased after chronic hypoxia, although maximum prostaglandin F2alpha-induced tension was unchanged, which implies a reduction in voltage-independent constrictor mechanisms. Although vasorelaxation to isoproterenol was depressed in arteries from hypoxic rats, forskolin-induced relaxation was enhanced substantially, and because the response to the phosphodiesterase inhibitor papaverine was unchanged, we suggest that this reflects an up-regulation of adenylate cyclase. In conclusion, chronic hypoxia resulted in a significant depolarization in small pulmonary arteries, but this may explain only partly the increased efficacy of voltage-dependent vasodilators. Whether the reduction in voltage-independent constrictor mechanisms is related to the apparent up-regulation of adenylate cyclase remains to be elucidated.
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PMID:Membrane potential-dependent and -independent vasodilation in small pulmonary arteries from chronically hypoxic rats. 961 97

The antiplatelet activity of (6-[(3-methylene-2-oxo-5-phenyl-5-tetrahydrofuranyl)methoxy]quinol inone) (CCT-62) was determined in vitro in rabbit platelets. CCT-62 inhibited rabbit platelet aggregation and ATP release caused by thrombin (0.1 U/ml), platelet-activating factor (2 ng/ml), collagen (10 microg/ml), arachidonic acid (100 microM), and 9,11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F2alpha (1 microM) in a concentration-dependent manner. The IC50 values for platelet aggregation were 18.4 +/- 4.5, 10.1 +/- 1.6, 3.0 +/- 0.9, 1.5 +/- 0.3 and 1.0 +/- 0.3 microM, respectively. In addition, CCT-62 disaggregated the clumped platelets caused by these aggregation inducers. It also inhibited phosphoinositide breakdown and intracellular calcium elevation induced by the above platelet aggregation inducers. CCT-62 increased intracellular cyclic AMP and cyclic GMP levels in a concentration- and time-dependent manner. Furthermore, it potentiated cyclic AMP formation caused by prostaglandin E1 but not that caused by 3-isobutyl-1-methylxanthine. CCT-62 did not affect adenylate or guanylate cyclase but inhibited cyclic AMP- and cyclic GMP-phosphodiesterase activities. The antiplatelet effect of CCT-62 was reversed by a protein kinase A inhibitor, N-[2-(P-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89). This data clearly indicated that CCT-62 is an inhibitor of phosphodiesterases and that its antiplatelet effect is mainly mediated by elevation of cyclic AMP levels.
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PMID:Cyclic AMP and cyclic GMP phosphodiesterase inhibition by an antiplatelet agent, 6-[(3-methylene-2-oxo-5-phenyl-5-tetrahydrofuranyl)methoxy)quinol inone (CCT-62). 966 3

Experiments were designed to determine whether or not relaxations of coronary arterial smooth muscle to C-type natriuretic peptide (CNP) vary according to gender, and if so, to determine mechanisms for the differences. Rings of coronary arteries without endothelium from sexually mature male and female Yorkshire pigs were suspended in organ chambers for measurement of isometric force. Cumulative concentration-responses to CNP (10(-9)-10(-7) M) were obtained in the absence and presence of either K+ channel blockers (charybdotoxin, apamine, or glibenclamide, 10(-7) M) or the clearance-receptor antagonist C-ANP (10(-6) M) during contractions to prostaglandin F2alpha (2 microM). Relaxations to CNP were significantly less in arteries from male compared with female pigs and were significantly attenuated by charybdotoxin and glibenclamide in both sexes. However, apamine reduced relaxations to CNP only in arteries from female pigs. C-ANP significantly potentiated relaxations to CNP only in arteries from male pigs. In separate experiments, cyclic guanosine monophosphate (cGMP) was measured by radioimmunoassay at specified times after the addition of CNP (10(-7) M). Peak increases in cGMP were greater and occurred earlier in arteries from female than from male pigs; these differences were eliminated by the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (10(-4) M). These results demonstrate three mechanisms that contribute to gender differences in CNP-mediated relaxation of coronary arterial smooth muscle: activation of low conductance Ca2+-activated K+ channels, natriuretic peptide clearance receptors, and activity/regulation of phosphodiesterases.
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PMID:Gender and relaxation to C-type natriuretic peptide in porcine coronary arteries. 967 14

We synthesized various 4-benzylamino-1-chloro-6-substituted phthalazines (15) and 4-benzylamino-1-chloro-7-substituted phthalazines (16) and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) purified from porcine platelets. The PDE5-inhibitory activities of 15 were greater than those of the isomers (16). The preferred substituent at the 4-position of phthalazine was a (3-chloro-4-methoxybenzyl)amino group, and those at the 6-position were cyano, nitro, and trifluoromethyl groups. Compounds 15a (IC50 = 4.8 nM), 15f (3.5 nM), and 15i (5.3 nM) were more potent inhibitors than E4021 (8.6 nM). Compounds 15a and 15f also showed vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F2alpha (10(-5) M). The EC50 values for vasorelaxant action of 15a, 15f, and E4021 were 150, 160, and 980 nM, respectively. These results show that novel PDE5 inhibitors possessing a potent vasorelaxant effect may exist among phthalazine derivatives.
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PMID:4-Benzylamino-1-chloro-6-substituted phthalazines: synthesis and inhibitory activity toward phosphodiesterase 5. 971 89

The effect of high concentrations of melatonin, and related indole-based and naphthalene-based derivatives, has been examined in the porcine coronary artery, pulmonary artery and the marginal artery of the colon. In addition, we have pharmacologically examined the role of cyclic GMP in the relaxatory action of these agents. Cumulative addition of melatonin (3-300 microM) caused a slowly developing relaxation in all three vascular preparations pre-contracted with 9,11-dideoxy-9a,11a-methanoepoxy prostaglandin F2alpha (U46619), a thromboxane mimetic agent. The estimated pIC50 values were 4.10-3.70 (coronary artery), 3.89 (pulmonary artery) and 3.96 (marginal artery). All melatonin analogues examined also produced concentration-dependent inhibition of U46619-induced contractions of the coronary and marginal arteries in a qualitatively similar manner to melatonin. The rank order of potency (based on the pIC50 values) of these compounds in both vascular tissues was N-[2-(3-ethyl-7-methoxynaphthyl) ethyl]-acetamide (S21634) >2-iodomelatonin = N-[2-(7-methoxynaphth-1-yl)-ethyl]-acetamide (S20098) = N-[2-naphth-1-yl-ethyl]-cyclobutyl carboxamide (S20928) >melatonin >N-acetyl-5-HT. Finally, the pharmacological characteristics of melatonin and S21634 as phosphodiesterase inhibitors were compared to those of zaprinast, a known cyclic GMP-specific phosphodiesterase inhibitor. Zaprinast also caused concentration-dependent inhibition of U46619-induced tone. All three compounds, zaprinast (10 microM), melatonin (300 microM) and S21634 (30 microM), significantly enhanced sodium nitroprusside-induced relaxations. The inhibitory action of zaprinast per se was greater in the presence of the endothelium and significantly attenuated by 3 microM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), a selective inhibitor of guanylyl cyclase. In marked contrast, the vasorelaxant action of melatonin and S21634 was not affected by the removal of the endothelium or the addition of ODQ. In summary, we have shown that porcine arterial smooth muscle relaxes in response to high concentrations of melatonin and other related melatonin receptor ligands. However, it appears that the receptive site is pharmacologically different from the melatonin receptors currently known and does not involve inhibition of cyclic GMP-specific phosphodiesterase.
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PMID:Pharmacological studies on the inhibitory action of melatonin and putative melatonin analogues on porcine vascular smooth muscle. 1073 Oct 47

We synthesized various 4-(3-chloro-4-methoxybenzyl)aminophthalazines substituted at the 1- and 6-positions and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) and their vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F2alpha (10(-5) M). The preferred substituents at the 1-position of the phthalazine were 4-hydroxypiperidino, 4-hydroxymethylpiperidino, 4-(2-hydroxyethyl)piperidino, and 4-oxopiperidino. Among these compounds, [4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxy)piperidino]-6-phthala zinecarbonitrile monohydrochloride (13) exhibited potent PDE5 inhibitory activity (IC(50) = 0.56 nM) with >1700-fold high selectivity over other PDE isozymes (PDE1-4). Compound 13 exhibited the most potent vasorelaxant action (EC(50) = 13 nM) in this series of compounds. Compound 13 reduced mean pulmonary arterial pressure by 29.9 +/- 3.1% when administered intravenously at 30 microg/kg to the chronically hypoxic rats and had an apparent oral bioavailability of about 19.5% in rats and was selected for further biological evaluation.
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PMID:4-(3-Chloro-4-methoxybenzyl)aminophthalazines: synthesis and inhibitory activity toward phosphodiesterase 5. 1089 Nov 11

The present study was aimed to elucidate the cellular pathway(s) controlling vascular relaxation triggered by stimulation of prostaglandin I2 (PGI2, IP) receptor with a stable PGI2 analog, beraprost. Beraprost caused a concentration-dependent relaxation in de-endothelialized guinea-pig aorta contracted with prostaglandin F2alpha (PGF2alpha). Beraprost-induced relaxation was almost abolished in high-KCl-contracted tissue, indicating a major role of K+ conductances. In contrast to other PGI2 analogs (e.g. cicaprost and iloprost), beraprost-induced relaxation was practically abolished by a selective voltage and Ca2+-activated K+ (MaxiK, BK) channel blocker Iberiotoxin (10(-7) M) or by tetraethylammonium (2 x 10(-3) M). The relaxation induced by beraprost was not significantly affected by other K+ channel blockers glibenclamide (10(-6) M) or Ba2+ (10(-5) M), but was slightly attenuated by 4-aminopyridine (10(-4) M). Beraprost increased intracellular cyclic AMP levels, suggesting a role for cyclic AMP-dependent pathways. A selective inhibitor of cyclic AMP-specific phosphodiesterase, RO-20-1724 (10(-4) M), significantly potentiated beraprost-induced relaxation. Iberiotoxin (10(-7) M) completely counteracted this potentiation. Moreover, tension decrement due to forskolin (3 x 10(-7) M) or 8-bromo-cyclic AMP (10(-2) M) was thoroughly restored by Iberiotoxin (10(-7) M), confirming a role for a cyclic AMP-dependent mechanism. However, SQ 22,536 (10(-4) M), an adenylyl cyclase inhibitor, did not affect beraprost-induced relaxation though it almost totally inhibited the elevation of cyclic AMP contents induced by beraprost, suggesting the existence of an additional mechanism that is cyclic AMP-independent. Moreover, cholera toxin (CTX, 1 microg/ml for 6 h), which activates the stimulatory G protein of adenylyl cyclase (Gs), significantly suppressed PGF2alpha-induced contraction both in the absence and presence of SQ 22,536 (10(-4) M). Iberiotoxin (10(-7) M) was also capable of restoring the relaxation induced by CTX. These findings suggest that MaxiK channel plays a primary role in mediating smooth muscle relaxation following stimulation of IP receptor with beraprost in guinea-pig aorta. Both cyclic AMP-dependent and -independent pathways contribute to the MaxiK channel-mediated relaxation following IP receptor stimulation in this vascular tissue. Direct regulation of MaxiK channels by Gs may partly account for the cyclic AMP-independent relaxant mechanism.
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PMID:MaxiK channel-mediated relaxation of guinea-pig aorta following stimulation of IP receptor with beraprost via cyclic AMP-dependent and -independent mechanisms. 1177 9


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